Long-term pharmacokinetics of 2,2',4,4',5,5'-hexachlorobiphenyl (6-CB) in rats with constant adipose tissue mass

Abstract

Long-term (280 days) pharmacokinetics of 2,2',4,4',5,5'-hexachlorobiphenyl (6-CB) was studied in rats with constant adipose tissue mass. This was achieved by feeding the animals 50% of their mean ad libitum food intake. 6-CB was administered as a single iv injection of 0.6 mg/kg. Tissues and excreta were analyzed at various time points from 4 to 280 days. After the redistribution phase, all tissue concentrations declined with terminal half-lives of 431-478 days, and concentration in adipose tissue was 1000 times higher than in blood. The corresponding ratios were: for skin 40, lung 30, liver 25, brain 10, and muscle 10. From day 4 on only adipose tissue, skin, and muscle contained significant amounts of 6-CB. Between 2 and 4 weeks adipose tissue and skin reached a maximum corresponding to 68 and 15% of the dose, respectively. After 280 days these values declined to 38 and 7% of the dose. Fecal excretion during this period was 43% of the dose with a terminal half-life of 478 days. Polar metabolites (1.5% of dose) were detectable in urine only. Extrapolation of fecal excretion kinetics yields a total excretion value of 99% of the dose at infinite time. Thus, in the rat with constant adipose tissue mass, 6-CB shows first order kinetics with reversible storage and total excretion. This is in sharp contrast with the situation of increasing adipose tissue, i.e. ad libitum feeding, which is characterized by irreversible storage in adipose tissue and limited excretion.